Ether lipids are the focus of considerable interest as new anti-tumor drugs. This interest has become so great that the journal Lipids recently devoted an entire issue to the First International Symposium on Ether Lipids in Oncology. See Lipids 22 (11), 775-980 (1987) (hereinafter "Ether Lipids in Oncology").
The model for new ether lipid anti-tumor drugs is rac-1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (ET-18-OMe), which was synthesized by Weltzein and Arnold in 1967. See Ether Lipids in Oncology at 787. Among numerous noteworthy subsequent developments are the sulphur-containing phospholipids described in Bosies et al. U.S. Pat. No. 4,444,766, the phosphoric acid ester derivatives of 1,3-Dioxy propane disclosed in Hozumi et al. U.S. Pat. No. 4,426,525, the cyclimmonium salts disclosed (as platelet activating factor inhibitors) in Lee et al. U.S. Pat. No. 4,619,917, and the lipoidal amine disclosed by J. Wolff et al., Cancer Immunol. Immunother. 12, 97, 98 (1982).
Lipids are also of interest as protein kinase C inhibitors. Pioneering work in this area is reported in Bell, Loomis, and Hannun U.S. Pat. No. 4,816,450. As noted therein, inhibition of protein kinase C is useful in a variety of ways. Such inhibition can, for example, lead to inhibition of the oxidative burst in neutrophils, whereby an anti-inflammatory effect is achieved. Inhibition of protein kinase C can also lead to inhibition of differentiation and growth of cells and can thereby, and through other mechanisms, produce an anti-tumor effect. Hence, there is continuing interest in developing new protein kinase C inhibitors.
Quaternary amine-containing derivatives of glycerol have been suggested for purposes such as surfactants for pharmaceutical formulations, See European Pat. App. No. 187,702 (Chem. Abstracts 105, 178443), and as textile finishing agents, see French Pat. No. 1,561,630, but these suggestions do not relate to the use of lipids as biologically active agents.
The present invention is based on our ongoing research into the use of ether lipid analogs in oncology.